Oxitec Ltd – Written evidence (GMI0016)

This document represents written evidence provided by Oxitec Ltd. to the House of Lords Select Committee on Science and Technology Call for Evidence on Genetically Modified Insects.  Oxitec was acquired by Intrexon Corporation, an NYSE-listed public company with operations in North America and Europe, in August 2015.  Oxitec’s primary operations, including its research and development facilities, continue to be based in the United Kingdom.

Executive summary

Specific applications of genetically modified (GM) insect technology have the potential to contribute significantly to global solutions for pest control in public health and agriculture. The UK is already a global research leader in this field but moving forward, benefits will be realised only if there is an enabling policy environment and public acceptance.

Oxitec Ltd., which originated from Oxford University, is a pioneer in the field. To our knowledge we are the only company in the world producing and distributing GM insects. We have developed a genetic-based approach to controlling pest insect populations, without toxins or pesticides, building on the proven successes of the radiation-based Sterile Insect Technique (SIT) that has been used worldwide for over 50 years.  For more than a decade the Oxitec approach has employed tools of modern biotechnology in producing genetically modified (GM) male insects, for use in sterile release programmes. The offspring of these males inherit a self-limiting gene and have no continued presence in the environment, thereby reducing the pest population in a manner targeted exclusively toward the insect species, and avoiding the off-target effects and broad environmental consequences of applying chemical insecticides.

Oxitec’s flagship product, a GM Aedes aegypti mosquito used in controlling the principle vector of Dengue fever and Chikungunya virus, has received biosafety approval for commercial release in Brazil, and has been evaluated in open release trials in several other countries.  In every case the disease vector was reduced by >90%; an unprecedented level of control in comparison to current methods. To date more than 100 million Oxitec mosquitoes have been released worldwide with no reported adverse effects on human health or the environment.

Historically, malaria has been reported in the UK, and Aedes mosquitoes have vectored outbreaks of dengue and chikungunya in Europe within the last decade. Climate modelling predicts that insect vectors of human disease could further expand their range in Europe. Therefore the use of self-limiting GM insect technologies to control vectors of human disease could be foreseen in Europe.

On the agricultural side, the use of self-limiting GM insects has enormous potential for controlling damaging pests in a safe and species specific manner. In 2014 the United States Department of Agriculture (USDA) granted an environmental release permit for an Oxitec Diamondback moth strain, and in the same year, the National Biosafety Technical Commission of Brazil (CTNBio) approved a similar release trial for an Oxitec Medfly strain. These most recent regulatory milestones are allowing Oxitec to build on previous safety data collected in contained conditions and generate additional data in environmental situations that support product safety and demonstrate efficacy. All of this has been accomplished from a small home base in the UK by effectively leveraging partnerships with private and academic collaborators internationally, and funded principally through private investment and various individual, global and domestic funding initiatives. 

Moving forward, Integrated Pest Management (IPM) solutions will be instrumental in addressing pest pressures that are mounting in the face of increasingly ineffective chemical controls. IPM solutions have smaller environmental footprints and help to manage resistance in pest populations. The use of self-limiting GM insects is fully compatible with IPM, and is foreseen as playing an integral part of IPM approaches across applications, as well as in some crops, a standalone replacement for chemical controls.

Self-limiting GM insects are not the same as GM crops, which society has politicised in the EU. The majority of commercially available GM crops have been designed with traits for resistance to insect attack or herbicide damage, thus giving them a “fitness” advantage over other varieties. It is the fitness advantage of GM crops which confers an ability to persist in the environment over time.  Self-limiting GM insects are the complete opposite, being engineered with the greatest fitness disadvantage of all; not being able to reproduce effectively, and are therefore unable to persist in the environment.

Regulation should enable an evaluation of GM insects that is balanced and proportionate whilst maintaining protection for human health and the environment, such that informed decisions can be made about their use.  Science-based risk assessment should give foremost consideration to the properties of the final product rather that the technology that underlies its development.  Differentiating for example approaches which are expressly designed not to persist in the environment (e.g. self-limiting), from those which have intended persistence as a feature of their design (e.g. population replacement), could significantly streamline the evaluation processes.  A balanced and proportionate regulatory approach should also give appropriate consideration to potential benefits as weighed against risks, and potentially the cost of not using the intervention. The European regulatory approach to the oversight of GMOs is focused entirely on evaluating potential risks associated with GM technology, whereas other jurisdictions internationally have embedded mechanisms to balance risk evaluation within the broader context of benefits and alternatives. In informing regulatory approaches, international and regional guidance for risk evaluation, such as that from the World Health Organization (WHO) and the European Food Safety Authority (EFSA), should also consider fundamental differences in the core technologies used in GM insects (e.g. self-limiting vs persistent)  as a key parameter in risk evaluation.

As the UK is a leader among knowledge-based economies, with centres of innovation and academic excellence, we have cultivated an environment for investment in science. Informed government policy rightfully accounts for a breadth of civic interests, however, a disproportionate weighting given to pressure groups has the potential to create an innovation and economic void.   Large multinational companies have already removed their agricultural biotechnology research outside of the UK and EU because of this climate, and the recent proposed ban in Scotland on GM crop production continues the dangerous precedent in this regard.  It is sincerely hoped that developers of GM insects will not also be driven to leave the UK. 

Proportional and balanced consideration of disparate interests is critical and one such mechanism to facilitate this could be an ombudsman role for information accountability; to offer a neutral forum for the independent validation of pressure groups claims so that we may all have access to the facts. Such a mechanism would provide the public with an impartial assessment when questions surrounding the adoption of new technologies enter the public domain.

Given more than a decade of first-hand experience in the field of GM insects for safe and sustainable pest control, we welcome the opportunity to provide written evidence to the House of Lords Select Committee on Science and Technology. We appreciate the need for evidence-based discussion so that the UK is not left behind in understanding, regulating and applying new advances for global health and food security.

1.                Which human diseases, across the world, could be addressed through GM insect technology? Are there any human disease risks in Europe, particularly the UK, for which GM insects are under development?

i) In the UK insect-borne disease is sometimes considered as a threat affecting predominantly tropical countries. However this is not the case. Invasive mosquito species that carry disease are not new to the UK, and malaria cases have been recorded from Roman times up to the end of the 1st World War[1]. History teaches us what happened before can happen again. With global climate change modern records show that invasive species that carry human diseases are gaining footholds in Europe and the UK. The incidences of the disease they carry have also increased concomitantly with the arrival of these insects. Where the insect goes the disease follows.

ii) In the EU there has been a steady increase in invasive mosquitoes.   In 2012-13, a Dengue outbreak in Madeira caused more than 2000 local cases, leading to over 80 cases being exported to mainland Europe (Lourenco and Recker, 2014).  One of the species that transmits Dengue – the Asian tiger mosquito - has moved as far north as central France.  In October 2014, France confirmed 4 cases of locally-acquired Chikungunya in the southern city of Montpellier[2].  Chikungunya had been previously reported as well in the north-east of Italy in 2007, where 217 cases where identified (Liumbruno et al, 2008).  A recent modelling exercise performed and published in the journal BMC Public Health, in 2014, concluded that there is a significant probability that climate change will open the doors to dengue in mainland Europe (Bouzid et al, 2014).

iii) Being resident in the UK it is sometimes easy to forget that one of the biggest killers on the planet is still infectious disease, and that some of the most important infectious diseases globally are transmitted by a single class of insects, the mosquitoes. Vector-borne diseases[3] account for more than 17% of all infectious diseases, causing more than 1 million deaths annually[4], a global health challenge which could be addressed by supporting the development and implementation of new tools and solutions. Oxitec technology has proven to be significantly more effective than chemical pesticides alone in controlling mosquito disease carrying vectors[5], and is based on toxin-free genetic technology that leaves zero chemical residue after applications cease. The Oxitec technology relies on a ‘self-limiting’ gene which means that any insect carrying the gene, or the offspring of male insects released into the environment, are destined to die and do not persist in the environment. This genetic engineering technology is completely different to most GM crops, where the majority have been designed with traits which confer resistance to insect attack or herbicide damage, thus giving them a “fitness” advantage over other varieties. Self-limiting GM insects on the other hand, are given the greatest fitness disadvantage, as they are engineered to die after environmental release and mating. Self-limiting GM insects by nature are less ‘fit’ than their wild pest insect counterparts and are unable to persist in the environment. The core science used in all Oxitec insect applications has been described in many peer-reviewed publications (http://www.oxitec.com/category/publications/).

iv)  Oxitec has had huge success in controlling the principal mosquito vector of Dengue fever (Aedes aegypti), with significant reductions in the target vector mosquito population being seen it all trials to date3.  Dengue is a serious flu-like disease with complications that can leave long-lasting joint pain or result in haemorrhagic fever and mortality. There is no cure for dengue and the development of effective vaccines has been problematic. The World Health Organization (WHO) estimates[6] around 390,000,000 infections a year of Dengue, and ten-fold more are at risk of infection; half a million of these cases require hospitalisation, of which 2.5% of cases lead to mortality of mainly children.

v) The World Health Organisation (WHO) has classified human diseases that are transmitted by insect vectors. The table below identifies key diseases and their insect vectors that could potentially become invasive and threaten the health of people in the UK (sources; Medlock and Leach 2015; Vaux and Medlock 2015; Bouzid et al 2014; ECDC 2014[7]).

2. What are the possible livestock and agricultural crop applications of GM insects across the world? Of current livestock disease risks and agricultural insect pests that could be addressed through GM Insects, which should be the highest priority for Europe?

i) Modernisation of global agricultural systems has always been dynamic and embraced technological advance. Large-scale mechanization, biological selection, and the use of chemicals have been some of the key drivers of revolutionary change. As challenges with the early generation solutions to agricultural pests arise, such as resistance to chemicals or undesirable effects of residues, we must look to new generations of pest control solutions for continued modernization and effective pest control. The Food and Agriculture Organization (FAO) estimates that global food production must increase by 70% to meet the demands of 9.1 billion people by 2050[8]. Otherwise we are facing serious threats to global food security that if left unmet will have a broad destabilising effect. The challenge of sustainable agriculture is set on a backdrop of less arable land and fresh water with increased pressure from pests and global climate change. 

ii) Current pesticide registrations are decreasing due to more stringent oversight of environmental impacts, such as neo-nicotinoids being banned due to concerns about their effects on bee health, while new active ingredients are becoming harder to identify.  Insect pests are becoming resistant to applied chemistries, including some biotechnology traits that protect against insects in row crops such as corn, soy and cotton.

iii) Self-limiting GM insect technology for agricultural pests offers an alternative approach to pest control and is especially powerful where those pests are or have become resistant to other crop protection products. Oxitec recently published a paper with lead researchers at Cornell University (Harvey-Samuel et al, 2015) demonstrating the effectiveness of GM diamondback moths, carrying the Oxitec self-limiting gene, at both controlling populations, and reducing resistance genes carried in pest populations (in this instance against a pest moth that causes $4-5bn in damages and control costs every year for crops such as canola, rape, broccoli, cabbage, and other brassicas in the UK and around the world). Oxitec’s core technology is transferable to any insect pest that has the following characteristics:

o Sexual reproduction

o   Ability to rear the insects in rearing facilities

o   Ability to genetically transform the insect

o   Simple lifecycle with non-damaging males (ideally)

These characteristics are present in many of the most significant global pests of agriculture. In Europe, agriculture is under a heavy burden from invasive and local insect species that are difficult to control with pesticides, where application is limited by label instructions driven by maximum residue limits, and of course where de-registrations are driven by health and environmental considerations.

iv) Oxitec has demonstrated solutions for a number of these pests including the olive fly which has devastated the olive growers in Europe[9], the Mediterranean fruit fly which is considered the world’s most damaging fruit pest, and Drosophila suzukii (spotted wing drosophila) which is now affecting soft fruit growers in the UK. This pest was inadvertently introduced to Europe in 2009 and now threatens a £1.8 billion UK industry including strawberries and raspberries[10] [11].

v) In livestock, GM insects (and other arthropods) could be effective in controlling a range of vector-borne diseases, including tsetse fly-vectored trypanosomiasis in cattle (and humans), and brown ear tick-borne Theileria parva (which kills >1 million cattle per annum in Africa[12]). The house fly, Musca domestica, is a nuisance and pathogen-transmitting pest of livestock around the world, estimated to cause US $375 million per annum in agricultural losses in the US alone (Geden and Hogsette, 2001). The stable fly, Stomoxys calcitrans, is a painful biter of cattle and other animals, compromising animal welfare and causing very significant losses in cattle farming (US $2.2 billion in the US) (Taylor et al 2012).

vi) In Europe, house fly and stable fly are significant and difficult-to-control pests and the self-limiting GM insect approach could provide an effective management solution. In addition, midge-borne viruses – most notably bluetongue virus – have emerged in Europe in recent years, and represent a significant threat to livestock production across Europe, including the UK[13].

3. Are there likely to be opportunities provided by GM insects that cannot be provided by other approaches, such as biological control methods? How could GM insect approaches be complementary to existing Integrated Pest Management (IPM) programmes?

i) Biological control is principally deployed commercially in smaller scale and protected horticulture, and in the home gardening sector; biological alternatives are currently lacking for major applications[14].   Establishing parameters, such as balancing the population of the biological control agent and pest population can be difficult, and the costs of rearing biological control agents are often high as well. Self-limiting GM insects in mass release programmes analogous to the Sterile Insect Technique (SIT) (Dyke, 2005), offer species-specific, environmentally sustainable pest management that can dramatically reduce the pest population far below the levels of control seen with other biological control methods. Self-limiting approaches, such as provided by Oxitec, have been demonstrated as extremely efficacious at reducing pest populations to very low levels. Oxitec’s approach is complementary with other pest control strategies in the context of Integrated Pest Management (IPM), or Integrated Vector Management (IVM) approaches, and the economics of combination approaches are likely to be favourable according to Oxitec in-house models. The use of self-limiting GM insects offers a unique ability to manage, reduce and potentially eliminate insects that carry pesticide resistance genes, extending the longevity of chemical controls.

ii) In addition to the potential to control insect pest species already present in an area, including invasive environmental species beyond agriculture and public health applications, self-limiting GM insects could be used in programmes to prevent new incursions of invasive insect species.  At its core, the functionality of the system relies on the universal mate-seeking behaviour of male insects.  The potential to hold in readiness, self-limiting GM insects of species which pose a risk of invasive entry, for scale up to control potential infestations, or to establish control barriers[15] represents an opportunity that cannot easily be realised with current controls or biological organisms.  Invasive species can be itinerant in nature and having a self-limiting GM insect as a control measure against incursions, especially when it is at low levels, could help protect the UK from potential phytosanitary and zoonotic pest incursions.   Currently there may be significant public, regulatory and technical issues in testing and registering a GM insect to control a pest that is not already present in the country.

4. How appropriate are current EU and UK GMOs regulatory frameworks in addressing the issues raised by GM Insects? Are there lessons to be learnt from the regulation of GM insects in other countries such as Brazil?

i) The EU GMO regulatory frameworks and UK implementing regulations cover both contained use (effectively limited to use in physical structures) and deliberate release of all GMO’s and therefore have a broad remit.  For the purposes of contained use the regulations work well in the UK, with centres involved in genetic modification being registered by the Health and Safety Executive (HSE) and inspected periodically.  There are further additional requirements under UK phytosanitary and animal disease protection legislation that have to be complied with for the genetic modification of plant and animal disease vectors.  One such example is the requirement for mosquitoes to be registered under the Importation of Animal Pathogens Order, 1980 as they are “potential” vectors of animal disease, even if they are imported to the country as dead specimens. This appears to be anti-intuitive and requires significant compliance resourcing as each transfer of specimens has to receive permission from the Secretary of State.

ii) The deliberate release and “placing on the market” EC Directive 2001/18 is not fit for purpose i.e.; ensuring potential adverse effects on human health and the environment from genetically modified organisms are accurately assessed.  Directive 2001/18/EC on the deliberate release into the environment of genetically modified organisms has been shaped predominantly by experiences of GM crop assessment and the politicisation of the process has led to dramatically increased data requirements.   As can be seen from the EFSA Guidance document on GM animals this thinking is already spilling over to GM insects. Consequently any potential regulation for the use of GM insects at the EU level is currently likely to be prohibitively expensive, protracted, unpredictable and so resource intensive that any developers are unlikely to try such a registration.  The current regulatory framework is therefore neither enabling nor proportionate for GMO’s and especially not for GM insects that are expressly designed not to persist in the environment (self-limiting applications). Not only is the regulation itself not enabling it sends a negative message to the rest of the world that has less experience – “ if this can’t be regulated in the EU, how are we supposed to do it? “

iii) GM insects are being developed, and have received approvals for commercial scale use (e.g. self-limiting GM mosquitos in Brazil) for the control of mosquito vectors of human disease where existing controls are failing to provide adequate protection to human health.  These applications, were they to undergo evaluation in the EU would require a focus on vanishingly small potential risks, exclusive of potential benefits, as the current regulatory framework only allows consideration of potential risk scenarios.  The utility of a risk/benefit analysis has been identified as well by the Advisory Committee on Releases to the Environment (2013) in their input to the EFSA consultation on guidance on the environmental risk assessment of genetically modified animals.  Other health products are assessed on a risk-benefit balance in the EU; something missing from the EU and the UK systems for GMO’s. The use of a risk/benefit framework in regulation of GM insects could facilitate a rational debate and proportionate analysis of risk.

iv) There are unmet needs in agriculture and horticulture as well for which self-limiting GM insects are being developed, such as for control of the massively destructive olive fruit fly (see Section 2). Even in light of the enormous impact olive fly had on European olive producers in 2014[16], a recent application to Spain for a self-limiting GM olive fly was required to be withdrawn as the costs of confinement of the trial were prohibitive.

v) One of the principle benefits of self-limiting GM insect biocontrol is that it is species specific and only targets the pest of interest thereby avoiding the off-target effects and broad environmental consequences of applying chemical insecticides. The focus of the EU legislation fails to take into account these potential environmental benefits, when obvious synergies exist with other EU legislation. The Sustainable Use Directive (2009/128/EC) specifically requires farmers and horticulturalists to reduce their environmental reliance on chemical controls and develop Integrated Pest Management (IPM) alternatives.  The Department for Environment, Food and Rural Affairs- Chemicals Regulation Directorate (DEFRA/CRD) have a major R&D programme that helps promote IPM [17]., however as CRD regulates pesticides and certain biological control agents but not GM insects, there is no coordinated approach to considering  how non-chemical  GM insect biocontrol agents could be integrated into sustainable agriculture approaches. Lessons should be learnt from the regulation of biological control organisms as the use of self-limiting GM insects in sterile release programmes is effectively analogous to releasing a biological control organism into the environment (e.g. Mumford 2012). Instead developers of new approaches to pest control, such as the use of self-limiting GM insects, are hampered by the large data requirements and a lack of risk/benefit proportionality, a result of the current focus on the GM aspect (i.e. the development process) of the product in the current EU regulatory framework. Another way of considering this is that the product itself should be regulated on the basis of its characteristics, and not the process (GM) of making the product.

vi) In the exportation of GM insects out of the EU, for example to collaborative international partners, the implementation of the transboundary movement regulation (TBM) 1946/2003 is a further burden to UK business.  This is not because the intent of the regulation is undesirable; it is important that importing countries know that a GMO is being brought into their country for deliberate release, but this regulation has been based on requirements for trade in commodity goods and ensuing trade tariffs.  Any import of a GM insect for field release or commerce already requires the relevant permits from the importing country prior to shipment– to require the exporter to also supply largely the same information to the same authorities again in a different format, is not only redundant and burdensome, but also confusing to the importing agencies as they receive this information twice in different formats. To implement the transboundary movement regulations in the UK and the EU it should simply be sufficient to notify authorities with the relevant import and field release permits received from the importing country as part of the TBM notification.  This achieves the goal of the TBM regulations of advance informed consent, prevents confusion of the authorities and streamlines operations within business and government.

vii) Lessons learnt from others;

Globally, there are gaps and overlaps in approaches to the regulatory oversight of GM insects, as well as useful precedents from which perspective may be gained.

• Regulatory uncertainty, i.e. where governments need to pause for thought on how to regulate GM insects due to lack of precedent, provides a vacuum that is frequently exploited by pressure groups whose opposition to GM technologies does not appear to be science-based. The process of regulatory evaluation as the gatekeeper should be respected and the outcome honoured; a good example is the Australian regulatory system.

• Considerable uncertainty and delay can be added to the process as it is not always clear which legislative frameworks apply to GM insects.   GM insect targets are principally pest insects, some of which are subject to plant and animal quarantine actions, resulting in a complex mosaic of sometimes conflicting requirements. This has been especially challenging with GM mosquitoes as opposed to agricultural pests, as there are frequently multiple agencies operating under different legal jurisdictions, and experience has shown that submitting an application is sometimes the most effective means to clarify the regulatory pathway.  For agricultural pests, Oxitec encountered this in Spain, where the authorities took over 6 months to determine if they had the legal jurisdiction under the 2001/18/EC regulation to handle applications for GM olive fly. In Brazil a clear regulatory framework, based on plausible scientific pathways to harm and subsequent evaluation allowed the assessment of the dossier for commercial release in approximately 9 months from submission to approval.

• It is frequently forgotten that unlike crop plants, target insects for GM approaches in pest control scenarios are, in their wild form, generally harmful to human or animal health, or agriculture, or are not environmentally neutral, invading from other countries and displacing native species.  They are often already subject to controls using chemical, biological or other means.  Consequently evaluation should consider a comparison to existing control measures, and additionally, the cost of taking no action.  A good example of this is from the USA, where under the National Environmental Policy Act, agencies are required to issue an Environmental Assessment that takes into consideration the alternatives available alongside the GMO application.  In an example, if GM mosquitoes were to be used in a sterile release based control program then they could be assessed against the current chemical controls (which are more damaging to beneficial insects and less effective on the target pest), as well as the availability (or lack) of therapeutic interventions such as vaccines.  Comment periods for applications, would then provide the opportunity for public input to regulatory authorities based on a balanced presentation of risk data, as well as benefit scenarios.  This was also a consideration in Brazil for the use of a GM mosquito (Aedes aegypti OX513A), where dengue fever is endemic and new solutions are urgently sought due to the increasing ineffectiveness of chemical control methodologies.

• GM insect biological control agents, such as those developed for population control in agricultural applications, could conceivably, depending on the specific design of the insect, result in low level presence of non-viable GM material on a small proportion of the harvested crop.  Although regulatory tolerances for insect damage in product destined for both the fresh market and for processing are almost always in place, and buyer specifications in some cases may exceed regulatory tolerances, these tolerances are often not zero, and the low level presence of residual GM insect material may pose a challenge for food safety regulators.  The US-FDA has in place the Early Food Safety Evaluation System for New Non-Pesticidal Proteins Produced by New Plant Varieties Intended for Food Use[18].  This system allows a prior food safety evaluation for GM crops in field trials under regulatory permit, such that any inadvertent traces in product destined for consumption, triggers a balanced regulatory response in light of a previously evaluated risk to human health.  Such an approach to the evaluation of GM insects for use in agricultural pest control applications could be appropriate, especially at the early trial stage, as the potential for excessively damaging regulatory actions (product recalls, trade barriers) exists when food safety aspects remain unassessed and unapproved GM events enter the food supply. This may also require a change in legislation in the EU as the current threshold for tolerance of unapproved events is zero; not a biologically relevant parameter either.

5. Do the World Health Organisation (WHO) guidelines on the release of GM mosquitoes provide the basis of an effective regulatory framework? How should issues regarding the emergence of resistance be considered?

i) The WHO guidelines on the release of GM mosquitoes (GMM) issued in 2014 have had a long and thoughtful gestation from a broad group of scientists skilled in various fields.  They aim to support informed and thoughtful development processes drawing on evidence from other public health applications such as insecticides, vaccines and other tools including biocontrol methods and agricultural practices. Whilst they draw on these aspects they also include public engagement and transparency needs during the research.  Several key aspects in the document are welcomed:

• the recognition of the enormous global health burden that mosquito borne diseases cause;
• the framing of the testing evaluation to be considered on a case by case basis;
• risk-benefit analysis being a forefront consideration for decision making;
• the recognition of national sovereignty in decision making; and,
• the recognition that self-limiting technologies carry lower risks than those of modified mosquitoes incorporating gene drives and intending to be self-perpetuating.

However there are several aspects to the guidelines that could potentially hinder the implementation of mosquito control programmes using self-limiting GM technologies were it to be used alone as a basis of a regulatory system.

ii) The guidance document could be interpreted as a potential checklist for regulatory authorities. Each country/regulatory jurisdiction could consider that each step has to be conducted entirely independently, in the local context, without referring to data generated in other countries. The purpose of generating data is predominantly to identify whether the genetic insert has resulted in unintended or adverse changes linked to the endpoints in the risk assessment.  Redundancy in data generation does not increase the knowledge base on safety and adds expense, complexity and time to the potential deployment of these valuable innovations, especially as funding sources for GM mosquitoes are predominantly either philanthropic or venture capital based. One of the stated aims of the guidance was to provide consistency for regulators and users developing data, therefore data generated in one country should be portable (i.e. accepted by other countries).  The need to use the WHO guidance as a framework in its entirety through Phase 1 – Phase 4 has in fact already been suggested by some countries with which Oxitec is working, despite having sufficient data on the potential for unintended and adverse changes to achieve commercial biosafety registration in another country, and that evaluation being available publically in the Biosafety Clearing House[19] of the Biosafety Protocol to the Convention on Biological Diversity.

iii) Although the principle that self-limiting GM mosquitoes present less risk than self-sustaining applications is sprinkled throughout the WHO guidelines, it is not clearly articulated that the two approaches should have fundamentally different considerations when evaluating risk. There are already robust risk mitigation options for self-limiting approaches including halting releases or using conventional vector control methods, and not all risk considerations are universally relevant to all GM mosquitoes. There is an implicit risk of over burdening these technologies with this guidance, as the separation of self-limiting and self-sustaining requirements not clearly delimited. There is also an overemphasis on the measurement of disease outcomes for self- sustaining technologies; the control of the vector, the mosquito itself, should be considered a positive driver for the use of these technologies at a wider scale without having to demonstrate epidemiological outcomes.  No insecticide has to demonstrate an epidemiological outcome to obtain registration for wide-spread use.

iv) Overall, although probably not the intention, the WHO guidance document appears to present a restrictive, overly prescriptive, set of conditions for the analysis of GM mosquitoes that could load inappropriate testing burdens for certain applications (e.g. self-limiting technologies) as mentioned in the points above. Consequently meeting the requirements if taken in their entirety is unlikely to be affordable by either private or public entities that seek to conduct work in this area, thereby hindering the adoption of innovative solutions so desperately needed in the fight against devastating mosquito borne diseases.

How should issues regarding the emergence of resistance be considered?

vi) For self-limiting technologies one way of dealing with the emergence of resistance could be to address this at the level of mass-rearing and production.  A robust quality management system that allows the continual assessment and improvement of quality to ensure product specifications (and therefore the customers’ expectations) are consistent is desirable and may be required by regulators.  This has already been instigated and implemented at Oxitec. Insect product lines are routinely checked against known baselines for the genotype and the phenotype as well as mating competitiveness.  Deviations from the baselines are investigated, corrected where necessary and concluded. The quality system includes: in-process and laboratory quality controls, non-conformance control, equipment control, control of documents and records, change controls, staff training, and post-market surveillance methodologies which are audited both internally and externally.   Therefore Oxitec is confident that product going out of the factory door meets quality standards and customer expectations.   Furthermore as adaptive management of insect numbers and ongoing product assessment is part of product application in vector control programmes, any deviations in product performance could be readily identified and inform future actions.

6. Do the European Food Safety Authority (EFSA) guidelines on the environmental risk assessment of GM Insects for commercial use sufficiently address the different risks from population suppression and population replacement approaches?

How should the ecological risks and human benefits that might arise from the application of gene drive techniques to population replacement approaches be assessed?

i) The EFSA guidance on the environmental risk assessment of genetically modified insects has been developed as a tool to direct assessment activities under the legislative authorities of 1829/2003 EC on genetically modified food and feed, and 2001/18 EC on the deliberate release into the environment of genetically modified organisms. The risk assessment criteria thus elaborated in the EFSA guidance necessarily aligns with a regulatory framework which in itself may be less appropriate for certain GM insect applications, such as self-limiting approaches vs persistent population replacement (discussed in question 4 response).

ii) The EFSA guidance is evidently borne out of the decades of extensive experience regulators have gained from the assessment of GM plants, and resembles EFSA plant guidance (EFSA 2010) in both its specific areas of risk, and in process.  Across the guidance document the established and tested GM-crop centric approach to defining areas of risk is consistently apparent at its core.   Whilst this is convenient for regulators and allows some consistency at the agency, the use of such a framework to define risk assessment criteria for GM insects is a force fit; requiring that GM insects categorically be evaluated across seven specific areas of risk without consideration given to the final traits or characteristics manifested in the GM insect.  

iii)  In recent years, regulatory approvals have been secured globally (Brazil, Cayman Islands, Malaysia, and Panama) to allow evaluation of GM mosquitoes, which are self-limiting in the environment, in population suppression programs.   We believe these applications demonstrate significant promise in addressing global health challenges posed by mosquito borne diseases, with consistent suppression of target mosquito populations in all trials to date (e.g Harris et al 2012, Carvalho et al 2015, additional data pending publication).  Multiple agricultural applications for pest suppression approaches using the same core technology are ready for field evaluation, and regulatory approvals for field trials have been secured (USA - Diamondback Moth, Pink Bollworm; Brazil- Medfly).  These pest population suppression approaches depend on mass rearing and continued release of insects engineered expressly not to produce viable progeny, nor persist in the environment. This method is essentially an adaptation of the Sterile Insect Technique (SIT), which uses radiation induced sterility and has proven efficacious in both population control and eradication programs for well over 50 years (Dyck et al 2005). This highlights the fundamental difference between population suppression approaches using mass reared genetically “sterile” insects, and population replacement approaches.  The basis of genetic approaches to sterile insect release is engineered lethality, whereby insects are designed expressly not to persist in the environment, and require sustained releases in the context of a population control program; they are effectively “self-limiting” in the environment by design.  Population replacement approaches seek to achieve the opposite result, that is, engineered environmental persistence.  These fundamentally different approaches are entirely divergent in terms of the intended environmental fate of released insects, and the EFSA guidance does not recognize this in establishing the direction and ensuing evaluative criteria for the environmental risk assessment.  Approaches to risk assessment in the regulatory context would best consider at the outset, the intended environmental fate of released insects and whether the engineered traits are manifested to achieve that intended outcome. Approaches from the assessment of biological control organisms could also be considered.

iv) Population replacement approaches have the intended endpoint of environmental persistence as a feature of their design and they should necessarily be subject to an environmental risk assessment approach having greater focus on areas of risk regarding environmental persistence of the GM insect.    Across the defined areas of risk in the EFSA guidance, exposure in all risk areas should be evaluated with primary consideration given to the temporal backdrop when evaluating population replacement approaches.  Population replacement strategies result in potentially indefinite exposure of the environment to the introduced GM insect, where-as population suppression strategies using self-limiting genetic approaches generally result in transient exposure scenarios measurable in timeframes of days.  As environmental persistence is an intended trait in population replacement strategies, resulting in prolonged exposure to the environment, the specific areas of persistence and invasiveness, and the interactions of the GM insect with non-target organisms, should require rigorous assessment over appropriate timescales. 

v) At its core, population suppression technologies using sterile GM insect (i.e. self-limiting) approaches depend on the capacity of released male insects to a) mate with wild female insects, and b) pass on traits such that progeny are not produced or do not survive. Male GM insects used in current self-limiting approaches are not associated with vectoring disease, as in the case of mosquito applications (i.e. males do not bite), nor are they associated with crop damage in agricultural applications as it generally female oviposition, or egg laying, and subsequent larval development which results in crop damage.  In evaluating solutions to insect pest pressures in the face of alternatives, the male release strategy employed in self-limiting GM insect approaches has an evident advantage as the males do not cause damage, yet the mechanism does not exist in the EFSA guidance to give this appropriate weight.   Population replacement strategies using both male and female release need to be more rigorously assessed in regard to the environmental persistence of females, and risk weighed in the face of alternative approaches.

vi) Insect pests present significant challenges to both public health and agriculture, and promising solutions using self-limiting GM insects in release programs similar to proven SIT approaches are now available or well in the development pipeline.  These solutions will be slow to positively contribute to public health outcomes and benefit agricultural and stakeholders if inflexible approaches to regulatory oversight in the context of risk assessment are not broadly examined with an eye for reform.  Government policy makers and regulators must recognise that fully embracing solutions which can contribute to achieving broader government policy objectives in the areas of public health and agriculture requires adaptive approaches to regulatory oversight in risk assessment.

7. How is research into the development of GM insects currently funded? Are there opportunities to attract more private investment into this area?

i) In comparison to the benefits that GM insects may bring, and the clear scientific lead that the UK has in this area, UK funding for research into this area has been very low in the UK, and vanishingly scarce for translational capability for development from laboratory to market. The main developments have been funded through the Grand Challenges in Global Health programme (funded by the Gates Foundation and others) and private investment. In our experience a small amount of early stage funding has been invested by the BBSRC and Wellcome Trust. Some grant funding has also been provided by the Technology Strategy Board (now Innovate UK), but the benefit  can be substantially eroded for an SME as they lose the Research and Development tax credit on all grant related activity regardless of the level of grant funding.  Overwhelmingly the majority of funding tends to be for early stage research and is extremely limited for translational activities.  The consequence of this is a lack of funding leverage comfort in the eyes of investors. Further the lack of such funding bears testament to a politicised environment around GM activities in the UK/EU (especially where those developments are coming from the private sector), and this is a powerful disincentive to fund activities in the UK/EU despite the UK having a scientific, entrepreneurial and operational competitive advantage.

ii) From an Oxitec perspective the vast majority of funding for R&D in this field has come from private sources and specifically includes high net worth individuals with international exposure who appreciate the dire need for new solutions to mosquito borne diseases and the limitations of a continued reliance on an increasing narrow range of chemical insecticides. The other main avenue is the Gates Foundation who have funded several programmes in this area within the framework of their objective of reducing the burden of malaria.

iii) There are many challenges for getting a new science application off the ground to benefit as many people as possible.  Many years of funding are required before proof of concept is achieved. While there is a similar funding pathway to, say, health biotech companies the sheer novelty of the GM insect approach and the lack of benchmarks will put off many commercial investors.  In Oxitec’s case the primary initial funders were individuals and entities with a very strong social motive as well as a desire to earn a financial return.  Even now that the company is realizing commercial scale biosafety approval, it took a company like Intrexon Corporation, a US based enterprise with both significant financial resources and a singular forward-looking vision for the planet, to secure Oxitec’s ability to move these technologies forward.

iv) The major challenge here is that in Europe, society has allowed GM technology to become highly politicised in spite of the clear benefits the technology can bring. This politicisation of a technology genre means that any private investor must be prepared to lose their investment as the main barriers to advancement are not based around scientific, market need, economics or regulatory barriers but instead are political. Once political risk is added to the myriad of other challenges then new ventures become almost impossible to fund unless there is an overwhelming social conviction as to the importance of the technology from its investors.  An example of the politicisation of this technology could be seen recently in the announcement of the proposed Scottish ban on GM[20]. What investor will invest in an area when multiple years of funding can be swept away in a single political statement? 

v) However, the clear example of Oxitec hopefully will show entrepreneurs and investors that technical commercial and investor success can be gained in this area and it is to be hoped that new initiatives will come forth and the Oxitec benchmark will facilitate investment.

8. Given the possible public health benefits of GM insects, should the Government be funding their commercialisation? Would this result in a conflict of interest with regard to regulation of releases? If so, how might this be managed?

i) In our view Government and the UK would benefit from helping to fund commercialisation for a number of reasons;

• To keep a lead in a new technology area for the benefits of British science and the economy as a whole;
• to build capacity for combatting the likely health threat to mainland UK from invasive species as rising temperatures bring these species to the UK; and,
• to support public health of Britons and indeed others, in British overseas territories, which rely on tourism as the primary source of income.

ii) Britain is a knowledge-based economy with exceptional strengths in life sciences. We should support new technologies as they emerge to ensure British science gains a leadership position. Otherwise key leading positions (for example agricultural biotechnology, stem cell research, GM insects) will all be lost. Private investment cannot be relied on to bring these technologies through especially where there is a political dimension. In these areas it is society’s failing that has allowed an un-level playing field so Government should assist to level it up.

iii) There is no conflict with regulation. Regulation should focus on the proportionate evaluation of safety and environmental aspects of a new product and equally consider the relevant risks and benefits.  The UK can lead here too ensuring that the regulatory process that is developed is fit for purpose and proportionate. Developing a commercial proposition for the technology in a foreign country is doubly difficult if it is not supported in the home country.

iv) Just as we rely on Government to both regulate and fund public health care, Government may be involved in these different areas for GM insects and other services created for the public good.

9. How could the UK benefit economically from both developing GM Insect technology and its use within the UK?

i) Britain can benefit from the direct economic returns in:

• Jobs;
• inward investment;
• exports;
• taxes; and,
• royalties for IP,

but it can also benefit from being recognised as a country that promotes both businesses and science and creates a climate for their development. At the moment Britain is renowned for invention and entrepreneurial flair but equally for underfunding of key technologies, a sensationalist media and ultimately selling our assets cheap abroad and losing out on the value created.  There has to be a very positive policy to prevent this from happening.

ii) At the moment Britain, compared to other countries, does not have a major imminent health threat from invasive species, but it is likely to arrive as insects adapt to more temperate environments and as temperatures rise, providing more opportunities for incursion. The Asian Tiger mosquito is a threat that is now causing a major health concern in France for example. By developing the capacity to address such eventualities they will be available to help if and when needed.

10. How can the gap between regulatory approaches and public concerns over GMOs be addressed? Is there a role for ‘responsible innovation’ approaches? What are the critical factors in effective public engagement from lab to final release?

i) Firstly, we need to distinguish between actual genuine public concerns and pressure group political activities. There is very little evidence of any public concern in the UK over GM insects and the overwhelming majority of independent media coverage is positive.  It is possible to find pressure group publicity and some sensationalist tabloid coverage but this is the exception. Looked at objectively, GM insects are being used to protect people from mosquito borne diseases, have the potential to reduce pesticide use, and contribute to sustainable agriculture. These are objectives that chime with public sentiment.

ii) The critical factor for any academic institution or company bringing forward a new technology is transparency and an ability to communicate with not only the science community but also with a broad stakeholder community such as politicians, media, local communities etc.   The Science and Media Centre, has helped to ensure that science-based stories are reported accurately in the media by facilitating access to high-quality independent scientific experts relevant to the story. This initiative should be strengthened and broadened by Government as they play a critical role in UK society.

iii) Society sets up independent evaluation mechanisms primarily through the regulatory process to ensure that any innovation is developed through a step by step process where each new step is preceded by the requisite level of data and proof to warrant the next step. Where risk management decisions are taken by political entities, this politicises the process. We should be careful not to develop new processes such as oversight for “responsible innovation” which create another level of bureaucracy, potentially stifling innovation. Also, we should ensure that the processes in place should enable participation by smaller, resource-limited developers and companies. If we over-regulate we alienate entrepreneurial innovation and value creation.

iv) Given that new technologies such as GM insects are likely to emanate from small companies with few resources rather than from large multinationals, the UK should consider a mechanism to provide a balanced perspective when pressure groups put information into the public domain and make claims as to its scientific validity.  Proponents of a new technology such as GM insects are subject to rigorous oversight by regulators, as well as scrutiny in the public domain; mechanisms to hold pressure groups accountable are needed to provide balance. In short, there are mechanisms in place that hold companies responsible and accountable - we need a mechanism to provide a similar accountability for pressure groups. 

Perhaps the UK should consider a ‘science information ombudsman‘ that could evaluate,  from an independent perspective, pressure groups claims and go on record as to their veracity.  The UK is a knowledge based economy with great expertise in life sciences - if the public loses faith in science it will be to the great detriment of our economy.

18 September 2015

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